Therapy for constipation

ABSTRACT

Compositions comprising colchicine and at least one amino-salicylic acid derivative, preferably olsalazine is used for treatment of prophylaxis of constipation.

This application is a 371 of PCT/AU98/00332 filed May 7, 1998.

1. Technical Field

This invention relates to methods and compositions for the treatment ofbowel disorders characterised by constipation. Such disorders includesegments of Irritable Bowel Syndrome (IBS) characterised byconstipation, chronic pseudo-obstruction, chronic abdominal bloatingsyndrome and functional constipation. Symptoms include abdominal pain,constipation, bloating, acid reflux, flatulence, nausea and vomiting,chronic lethargy and sleep disorders.

2. Background Art

Constipation is a very common condition in the west, affecting about 20%of the population. Yet, to date no effective therapy is available.Chronic constipation is a condition largely confined to women and is ofunknown etiology. Diet, psychology, motility disturbances and entericnervous dysplasia have been identified as possible causes or factors.However, for the majority of patients the cause of constipation remainsobscure. The pathogenesis of irritable bowel syndrome has also hithertobeen unknown. Conventional treatments have been unsatisfactory asinstanced by the very large number of therapies available andrecommended from time to time. These have included psychotherapy,dietary regimens, and laxatives. To date, there is no evidence that anysuch therapies influence the underlying mechanism of the disorder andcertainly cure is not possible.

In general, therefore, the treatment of constipation and bloating aswell as pseudo-obstruction and functional constipation depends still onchronic usage of laxatives. There has indeed been little attempt totreat any underlying pathophysiologic condition, since the underlyingcondition is not yet understood. However, as described by Borody T J etal (Oral vancomycin can reverse idiopathic constipation,Gastroenterology (1989) 96 52A) there is some evidence that inconstipated patients abnormal bowel flora may be invaded by yetuncharacterised pathogenic bacteria which manufacture falseneurotransmitters which bind to the nerves and muscle fibres of theenteric nervous system and affect intestinal motility. Constipation andpseudo-obstruction may ensue from such an infection. From clinicalobservations and response to antibiotics it is apparent that more oftenthan not constipation is caused by an infection of the normal entericflora by bacteria which manufacture endorphin-like substances.

However, use of antibiotics on a long-term basis has been of little helpin solving the problem of constipation because of potentialside-effects. For example, vancomycin is neurotoxic. Furthermore, costsof such antibiotics to the patient would be prohibitive.

More recently, colchicine, a drug used for several decades in thetreatment of gout and one known to cause diarrhoea, has been trialed insevere constipation (Verne G N et al: Colchicine is an effectivetreatment for patients with severe idiopathic constipation,Gastroenterology (1995) 108 A705). However, colchicine given alone inthe doses described in the paper is dangerous long-term since it cancause muscle and nerve damage (myopathy and neuropathy) and is thereforeof no practical use in chronic constipation. In a lower dose it isinsufficient in most patients to stimulate defecation. Hence, on its owncolchicine is clinically of interest but of no practical use for thisgroup of conditions.

Australian patent no. 652191 discloses the usefulness of salicylic acidderivatives in the treatment of bowel disorders including constipation.However, only larger doses of 1.0 to 1.5 g amino-salicylic acidderivatives effectively relieved the symptoms of constipation and thepercentage of patients whose constipation is actually ameliorated byadministration of amino-salicylic acid derivatives alone is relativelylow.

Accordingly, there remains a need for an effective therapy forconstipation. It is an object of the present invention to provide acomposition and method for the treatment of constipation.

DISCLOSURE OF THE INVENTION

The present invention arose from observations by the inventor thattreatment of patients with colchicine for constipation, althougheffective, requires high doses as does treatment with amino-salicylicacid derivatives. It was only upon combining both these agents at lowerdoses that it was observed that such a combination produces the bestresults to date for the patient. The clinical effect on the symptoms ofbowel disorders characterised by constipation, by combinedadministration of low doses of an amino-salicylic acid derivative andcolchicine, is surprisingly greater than would be expected from asummation of the known effects of administering the same doses of eitherthe amino-salicylic acid derivative or colchicine alone.

Thus, in a first embodiment, the invention provides a pharmaceuticalcomposition for the treatment or prophylaxis of constipation, thecomposition including or consisting of colchicine and at least oneamino-salicylic acid derivative.

In a second embodiment, the invention provides a method for thetreatment or prophylaxis of constipation in a mammal in need of saidtreatment or prophylaxis, including administering to said mammal aneffective amount of colchicine and an effective amount of at least oneamino-salicylic acid derivative.

The invention further provides a process of manufacturing a medicamentfor the treatment or prophylaxis of constipation, the compositionincluding or consisting of colchicine and at least one amino-salicylicacid derivative; use of a composition including or consisting ofcolchicine and at least one amino-salicylic acid derivative for thetreatment or prophylaxis of constipation; and use of colchicine with atleast one amino-salicylic acid derivative for the manufacture of amedicament for the treatment or prophylaxis of constipation.

As used herein, the expression “amino-salicylic acid derivative” means4-amino salicylic acid, 5-amino salicylic acid, or a pharmaceuticallyacceptable salt or prodrug thereof.

In the compositions, methods, processes and uses in accordance with theinvention, the amino-salicylic acid derivative is typically selectedfrom the group consisting of mesalazine (5-amino salicylic acid),olsalazine, sulfasalazine, ipsalazide, balsalazide, benzalazine,para-amino salicylic acid (4-amino salicylic acid) and pharmaceuticallyacceptable salts thereof.

Preferably, the amino-salicylic acid derivative is one of a groupconsisting of sulfasalazine, olsalazine and the amino salicylic acidsincluding 5-amino salicylic acid and 4-amino salicylic acid or apharmaceutically acceptable salt thereof. Still more preferably, theamino-salicylic acid derivative is selected from mesalazine, olsalazineand pharmaceutically acceptable salts thereof. Advantageously, theamino-salicylic acid derivative may be selected by reference to theparticular disorder involved. For example, pain-predominant constipationmay benefit more from administration of a preparation includingmesalazine as opposed to olsalazine. Compositions which includecolchicine and more than one amino-salicylic acid derivative are alsowithin the scope of the present invention. Similarly, a method of thesecond embodiment of the invention may include administering more thanone amino-salicylic acid derivative.

Compositions of the invention may be prepared by means known in the artfor the preparation of pharmaceutical compositions including blending,grinding, homogenising, suspending, dissolving, emulsifying, dispersingand, where appropriate, mixing of the colchicine and amino-salicylicacid derivative(s), optionally together with one or more selectedexcipients, diluents, carriers and adjuvants.

The pharmaceutical composition of the invention may be in the form of atablet, lozenge, pill, troche, capsule, soft-gel capsule, sachet orother combining vehicle, elixir, powder, including lyophilised powder,solution, granule, suspension, emulsion, syrup or tincture.Slow-release, or delayed-release, forms may also be prepared, forexample in the form of coated particles, multi-layer tablets ormicrogranules. The composition may also be presented in acompliance-enhancing blister pack.

Solid forms for oral administration may contain pharmaceuticallyacceptable binders, sweeteners, disintegrating agents, diluents,flavourings, coating agents, preservatives, lubricants and/or time delayagents. Suitable binders include gum acacia, gelatin, corn starch, gumtragacanth, sodium alginate, carboxymethylcellulose or polyethyleneglycol. Suitable sweeteners include sucrose, lactose, glucose, aspartameor saccharine. Suitable disintegrating agents include corn starch,methylcellulose, polyvinylpyrrolidone, xanthan gum, betonite, alginicacid or agar. Suitable diluents include lactose, sorbitol, mannitol,dextrose, kaolin, cellulose, calcium carbonate, calcium silicate ordicalcium phosphate. Suitable flavouring agents include peppermint oil,oil of wintergreen, cherry, orange or raspberry flavouring. Suitblecoating agents include polymers or copolymers of acrylic acid and/ormethacrylic acid and/or their esters, waxes, fatty alcohols, zein,shellac or gluten. Suitable preservatives include sodium benzoate,vitamin E, alpha-tocopherol, ascorbic acid, methyl paraben, propylparaben or sodium bisulphite. Suitable lubricants include magnesiumstearate, stearic acid, sodium oleate, sodium chloride or talc. Suitabletime delay agents include glyceryl monostearate or glyceryl distearate.

Liquid forms for oral administration may contain, in addition to theabove agents, a liquid carrier. Suitable liquid carriers include water,oils such as olive oil, peanut oil, sesame oil, sunflower oil, saffloweroil, arachis oil, coconut oil, liquid paraffin, ethylene glycol,propylene glycol, polyethylene glycol, ethanol, propanol, isopropanol,glycerol, fatty alcohols, triglycerides or mixtures thereof.

Suspensions for oral administration may further include dispersingagents and/or suspending agents. Suitable suspending agents includesodium carboxymethylcellulose, methylcellulose,hydroxypropylmethyl-cellulose, poly-vinyl-pyrrolidone, sodium alginateor cetyl alcohol. Suitable dispersing agents include lecithin,polyoxyethylene esters of fatty acids such as stearic acid,polyoxyethylene sorbitol mono- or di-oleate, -stearate or -laurate,polyoxyethylene sorbitan mono- or di-oleate, -stearate or -laurate andthe like.

Emulsions for oral administration may further include one or moreemulsifying agents. Suitable emulsifying agents include dispersingagents as exemplified above or natural gums such as gum acacia or gumtragacanth.

A composition of the first embodiment typically contains from 0.1 mg to3 mg of colchicine, more typically from 0.5 mg to 2.0 mg, even moretypically from 0.5 mg to 1.5 mg; and from 100 mg to 1000 mg, moretypically from 200 mg to 500mg, even more typically from 250 mg to 400mg of the amino-salicylic acid derivative.

For administration as a tablet or capsule, the colchicine andamino-salicylic acid derivative may be combined in powdered orgranulated form, for example by compression into a tablet or as afilling for a capsule. Alternatively, the composition of the firstembodiment may be provided in the form of a tablet/capsule containingone or both of the colchicine and amino-salicylic acid derivative in amicroencapsulated form. As another possibility, the composition of thefirst embodiment may be provided in the form of a tablet/capsulecontaining the colchicine or the amino-salicylic acid derivative in apowdered form, and the other in a microencapsulated form. As a furtherpossibility, the composition of the first embodiment may be provided inthe form of a tablet/capsule containing the colchicine and theamino-salicylic acid derivative each in a microencapsulated form. Ineven further possibilities, the composition of the first embodiment maybe provided in the form of a tablet containing the colchicine or theamino-salicylic acid derivative within a capsule containing the other, acapsule containing one of the colchicine or amino-salicylic acidderivative in a tablet of the other, or a capsule containing thecolchicine or the amino-salicylic acid derivative within an outercapsule containing the other.

Preferably, the amino-salicylic acid derivative is presented in a formwhich facilitates its release in the distal small bowel. For example, ina composition of the invention, the amino-salicylic acid derivative maybe provided with an enteric coating or provided in an enteric coatedrelease capsule, or enteric coated colchicine microencapsulatedparticles can be carried within a capsule of distally-releasingamino-salicylic acid, for example olsalazine. When the colchicine isadministered in a relatively high dosage, such as for example 1.5 mg perday or more, it is essential that the colchicine be enterically coated.

Suitable materials for enteric coating are known in the art and includevarious synthetic resins bearing carboxyl groups, phenyl salicylate, andshellac. Examples of such enteric coating materials are polymethacrylicacid and methacrylic acid copolymers such as methacrylic acid—acrylicacid ester copolymers; modified cellulose esters such as hydroxypropylcellulose phthalate, hydroxypropyl methylcellulose phthalate, ethylcellulose phthalate, methyl cellulose phthalate and mixtures thereof,cellulose acetate phthalate, hydroxypropyl methylcellulose succinate,ethyl cellulose succinate, methyl cellulose succinate and mixturesthereof, cellulose acetate trimellitate, cellulose ether phthalates; andpolyvinyl acetate phthalate, succinate or trimellitate. A preferredenteric coating is Opadry OY-P 22920, available from Colorcon, 415 MoyerBlvd, West Point, Pa. 19486, United States of America. Entericfilm-forming compositions are described, for example, in U.S. Pat. Nos.4,556,552 and 4,704,295, the disclosures of which are incorporatedherein by reference.

The method of the second embodiment provides a method for the treatmentof constipation. The constipation may be associated, for example, withconstipation-predominant IBS, pseudo obstruction or functionalconstipation.

In the method of the second embodiment, the mammal is typically a human.

In a method of the second embodiment, the colchicine and amino-salicylicacid derivative may be taken once, twice, three times a day or morefrequently. The dosages may range for colchicine from 0.1 mg through to5 mg per day, more typically 0.5 mg to 5 mg per day, still moretypically 0.5 to 3 mg per day. The 5-ASA compound dosage may vary from100 mg through to 5 g per day, more typically 200 mg to 4 g per day,still more typically 500 mg to 2 g per day.

Usually, the colchicine and the amino-salicylic acid derivative areadministered twice daily. As a general rule for long term therapy thedosage may commence at a low level, such as daily and may be elevated toa higher dosage, such as twice or three times daily if required.Administration is typically over a period of from 30 days to 60 days ormore, including indefinitely for the lifetime of the patient. Moretypically, a method of the invention results in relief of symptoms whenthe colchicine and the amino-salicylic acid derivative are administeredover a period of from 60 days to 120 days. After relief or symptoms isachieved, administration of the colchicine and amino-salicylic acidderivative may be ceased, tapered, or reduced to lower maintenancedosages for an indefinite period.

Thus, a further form of the invention provides a pack including aplurality of compositions of the first embodiment in individual dosageshaving different amounts of the colchicine and the amino-salicylic acidderivative, the compositions being packaged in such a way that dosagesof the colchicine and the amino-salicylic acid derivative are takenaccording to a predetermined schedule by a person to whom the dosagesare administered.

For example, the compositions may be packaged in a blister pack in astrip, circle, or other arrangement facilitating sequentialadministration, with instruction that the compositions are to be takenby the patient in a particular order, commencing with a particularposition in the pack. For example, if the compositions are packaged in astrip, typically administration commences with the first composition atone end of the strip and continues with successive compositions packagedalong the strip, the amounts of colchicine and amino-salicylic acidderivative in the successive compositions varying according to apredetermined dosage regime. Other similar arrangements will suggestthemselves readily to persons of ordinary skill in the relevant art.

Without wishing to be bound by any theory, it is postulated by thepresent inventor that both colchicine and amino-salicylic acidderivatives, such as 5-amino salicylic acid, are capable of secretingwater into the bowel and are probably capable of suppressing abnormalbowel flora bacteria. Colchicine has anti-tubilin action and henceinhibits bacteria. 5-amino salicylic acid is a known antimicrobial agentsimilar to para-amino salicylic acid.

Best Method and Other Methods of Carrying Out the Invention

One preferred composition in accordance with the invention consists of375 mg of olsalazine in a capsule also containing 0.8 mg of entericallycoated colchicine. For example, the enterically coated colchicine may beobtained by microencapsulating a suitable quantity of granules ofcolchicine with Opadry OY-P 22920.

An alternative preferred composition in accordance with the invention isa capsule containing 375 mg of olsalazine and a 0.5 mg tablet ofcolchicine enterically coated with Opadry OY-P 22920.

In a preferred method in accordance with the invention for the treatmentof severe constipation, a patient is administered with twice daily dosesof 375 mg of olsalazine and 0.8 mg of enterically coated colchicine.Administration is continued twice daily until defecation is achieved. Apatient with mild constipation may be administered once daily doses, inthe morning, of 375 mg of olsalazine and 0.8 mg of enterically coatedcolchicine, whereas some patients with obstinate constipation mayrequire three doses or more per day.

An enteric coating on the colchicine prevents the colchicine from beingabsorbed in the small bowel and reduces the danger of over-dosage. Hencethe danger of the serious effects of overdose of colchicine which areknown is avoided. In the colon, from which colchicine is not absorbed,it acts upon the bacteria relevant to constipation.

EXAMPLE

Composition Including 375 mg Olsalazine and 0.5 mg Colchicine

A. Enterically coated colchicine 0.5 mg tablets

1 kg of 100 mg tablets containing 0.5 mg colchicine (Colgout 0.5 mgtablets, Fisons Parmaceuticals) are sprayed in a suitable spray-coatingapparatus with a 15% w/w solution of Opadry OY-P 22920 in aqueousethanol (about 80% ethanol v/v) at an inlet air temperature of about70-75° C. until the weight gain of the tablets is at least 8% of theweight of the uncoated core tablets.

B. Capsules of olsalazine and enterically coated cochicine

Capsules containing a coated tablet obtained from step A and a capsuleof 375 mg olsalazine are prepared by conventional methods.

Case Studies

Case Study 1

A 48 year old patient who had been investigated for chronic abdominalpain, slow transit constipation with defecation occurring once a week,bloating, nausea and recurrent headaches was referred for treatmentsince she had failed to have symptoms controlled with anti-spasmodicsand laxatives. Colonoscopy and stool cultures were all normal. In spiteof the use of added fibre and laxatives together with antispasmodics andprokinetics she continued to suffer with her original symptoms. She wascommenced on colchicine 0.5 mg twice daily together with olsalazine250mg twice daily. Within 10 days of commencement of the treatment thepatient began to defecate and by 3 weeks she was defecating normallywith a marked reduction of abdominal pain, bloating and nausea. She wasable to continue with the same relief on daily treatment for over 8months.

Case Study 2

A 64 year old male who presented with bloating, abdominalpain—especially left iliac fossa, and defecation occurring every fourthto fifth day was referred alter previous investigations including stooltests, colonoscopy and transit studies had been carried out. He hadslight transit constipation and had failed treatment with combinedlaxatives. This patient was commenced on colchicine 1 mg twice daily,together with olsalazine 250 mg twice daily. He began to defecatenormally by 14 days and then to develop some loose motions. Thecolchicine was decreased to 0.5 mg in the morning and 1 mg at night andthe olsalazine was continued at 250 mg twice daily. The patient'sabdominal distension, abdominal pain and constipation werewell-controlled. He continued the medication for 12 months, at whichtime reduction of the medication and ultimately ceasing the medicationdid not result in any recurrence of constipation. 3-6 months afterceasing medication the patient was not as loose as before, but he wasable to defecate relatively normally every day or every second day. Thiscase provides an indication that the composition and method of thepresent invention can reverse the underlying problem; that is it canpossibly eradicate or suppress the pathogenic bacteria that causeconstipation.

Case Study 3

A 48 year old female suffering from chronic constipation, bloating andcramps was treated with olsalazine 250 mg twice per day and uncoatedcolchicine 0.5 mg 3 times per day. After about 10 days defecationcommenced and the bloating and cramps were relieved. The regimen waschanged to enterically coated colchicine 0.5 mg 3 times per day, witholsalazine continuing at 250 mg twice per day. The patient subsequentlyexperienced loose motions and the colchicine was reduced to 0.5 mgenterically coated twice per day with maintenance of the olsalazine 250mg twice per day. Following this change, the patient experienced normalmotions and there was no loss of relief of the bloating and cramps.

What is claimed is:
 1. A dosage form for use in the treatment orprophylaxis of constipation, comprising olsalazine present in an amountranging from 100 mg to 1000 mg and colchicine present in an amountsynergistically interacting with the olsalazine in the range of 0.1 mgto 3 mg.
 2. A dosage form according to claim 1, comprising from 0.5 mgto 1.5 mg of colchicine and from 250 mg to 500 mg of olsalazine.
 3. Adosage form according to claim 2, comprising from 0.5 to 1 mg ofcolchicine and from 250 mg to 500 mg olsalazine.
 4. A method for thetreatment or prophylaxis of constipation in a mammal in need of saidtreatment or prophylaxis, comprising administering to said mammal from0.5 mg to 3 mg per day of colchicine and from 500 mg to 2 gm per day ofolsalazine.
 5. The method according to claim 4, comprising administeringsaid mammal from 0.5 to 2 mg per day of colchicine and from 500 mg to 2gm per day of olsalazine.